Adoptive MHC-E-Restricted T Cell Therapy for the Treatment of Chronic Hepatitis B Virus Infection

项目总结 慢性乙型肝炎病毒感染(CHB)被认为是一个主要的全球健康问题。CHB影响247 全世界有100万人，每年有88.7万人死于相关的肝脏并发症。如此高的发病率 而且，慢性乙肝的治疗方法很少治愈，这一事实加剧了死亡率。因此，仍然存在一个 迫切需要开发新的慢性乙肝治疗方法，以消除或持久抑制 感染。 在这里，我们提出了一种通过使用MHC-E限制性CD8T细胞来靶向乙肝病毒的新方法。这里只有 人类群体中的两个MHC-E等位基因，它们在功能上是等价的。因此，乙肝病毒特异性 MHC-E限制的CD8T细胞对所有CHB患者均有效。我们将描述T细胞的特征 恒河猴巨细胞病毒载体接种后MHC-E限制性CD8 T细胞受体的研究 这就产生了大量的这些独特的反应。然后我们将测试这些TCR的能力 识别和抑制乙肝病毒感染。鉴于对易治疗的慢性乙肝疗法的迫切需求，我们相信 这里提出的研究具有最高的意义。

PROJECT SUMMARY Chronic hepatitis B virus infections (CHB) are recognized as a major global health concern. CHB affects 247 million people worldwide, and 887,000 die annually from associated liver complications. This high morbidity and mortality is exacerbated by the fact that treatments for CHB are rarely curative. Thus, there remains an urgent need to develop new therapeutic treatments for CHB that will lead to clearance or lasting suppression of infection. Here, we propose a new way to target HBV through the use of MHC-E-restricted CD8+ T cells. There are only two MHC-E alleles within the human population and they are functionally equivalent. Therefore, HBV-specific CD8+ T cells restricted by MHC-E should be effective in all patients with CHB. We will characterize the T cell receptors (TCRs) of MHC-E-restricted CD8+ T cells in rhesus macaques inoculated with a rhesus CMV vector that engenders large numbers of these unique responses. We will then test the ability of these TCRs to recognize and suppress HBV infection. Given the urgent need for tractable CHB therapeutics, we believe the research proposed herein to be of the highest significance.